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Epithelial resilience mechanisms to environmental nanoparticles in health and disease are poorly characterised.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We delineated the impact of prevalent pollutants such as carbon and zinc oxide nanoparticles, on cellular function and progeny in primary human bronchial epithelial cells (pHBECs) from end-stage COPD (COPD-IV, n=4), early disease (COPD-II, n=3) and pulmonary healthy individuals (n=4). After nanoparticle exposure of pHBECs at air\u2013liquid interface, cell cultures were characterised by functional assays, transcriptome and protein analysis, complemented by single-cell analysis in serial samples of pHBEC cultures focusing on basal cell differentiation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>COPD-IV was characterised by a prosecretory phenotype (twofold increase in MUC5AC<jats:sup>+<\/jats:sup>) at the expense of the multiciliated epithelium (threefold reduction in Ac-Tub<jats:sup>+<\/jats:sup>), resulting in an increased resilience towards particle-induced cell damage (fivefold reduction in transepithelial electrical resistance), as exemplified by environmentally abundant doses of zinc oxide nanoparticles. Exposure of COPD-II cultures to cigarette smoke extract provoked the COPD-IV characteristic, prosecretory phenotype. Time-resolved single-cell transcriptomics revealed an underlying COPD-IV unique basal cell state characterised by a twofold increase in KRT5<jats:sup>+<\/jats:sup>(<jats:italic>P<\/jats:italic>=0.018) and LAMB3<jats:sup>+<\/jats:sup>(<jats:italic>P<\/jats:italic>=0.050) expression, as well as a significant activation of Wnt-specific (<jats:italic>P<\/jats:italic>=0.014) and Notch-specific (<jats:italic>P<\/jats:italic>=0.021) genes, especially in precursors of suprabasal and secretory cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We identified COPD stage-specific gene alterations in basal cells that affect the cellular composition of the bronchial elevator and may control disease-specific epithelial resilience mechanisms in response to environmental nanoparticles. The identified phenomena likely inform treatment and prevention strategies.<\/jats:p><\/jats:sec>","DOI":"10.1136\/thorax-2022-219958","type":"journal-article","created":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T18:25:17Z","timestamp":1706552717000},"page":"524-537","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":15,"title":["COPD basal cells are primed towards secretory to multiciliated cell imbalance driving increased resilience to environmental stressors"],"prefix":"10.1136","volume":"79","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1288-809X","authenticated-orcid":false,"given":"Mircea 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